The present invention relates, in general, to a method of preventing or treating human immunodeficiency virus (HIV) infection, and in particular, to a method of preventing or treating HIV infection using a cobalamin. The invention further relates to compositions suitable for use in such a method.
HIV-1 causes the disease designated acquired immunodeficiency syndrome (AIDS). HIV-1 infects both lymphocytes and mononuclear phagocytes. Many of the infection of lymphocytes results in cell death and thus in a severe depletion in lymphocyte number. Infected mononuclear phagocytes apparently do not die, but rather remain in tissues as reservoirs of the HIV-1. HIV-1 infected mononuclear phagocytes not only serve as reservoirs of the virus, but they also are thought to elaborate toxic materials that cause (or contribute to) problems such as HIV-1-associated neurodegenerative disease. Also, HIV-1 infection of mononuclear phagocytes reduces the ability of these cells to perform their normal host defense functions, such as mediation of resistance to infection by intracellular organisms (e.g. Cryptococcus neoformans) and mediation of resistance to tumor development and growth.
Productive cellular infection with HIV-1 is controlled by various viral and host cell factors (Greene, New Eng. J. Med. 324:308 (1991); Fauci, Ann. Int. Med. 114:678 (1991); Weinberg, Current Opin. Hematol. 1:138 (1993)). Although recent work has demonstrated that nitric oxide (NO) can exert an anti-viral effect on DNA viruses (Croen, J. Clin. Invest. 91:2446 (1993); Karupiah et al, Science 261:1445 (1993)), inhibition of HIV-1 infection by NO has not been reported. Phagocyte production of NO has, however, been observed. For example, human mononuclear phagocytes can, after appropriate stimulation, produce low levels of NO (Denis, J. Leuk. Biol. 49:380 (1991); Zembala et al, Eur. J. Immunol. 24:435 (1994); Martin et al, J. Immunol. 150:3478 (1993); Pietraforte et al, J. Leuk. Biol. 55:175 (1994); Kolb et al, J. Biol. Chem. 269:9811 (1994); Hunt et al, Journal of Hepatology 14:146 (1992); Munoz-Fernandez et al, Immunol. Letters 33:35 (1992)). Further, Bukrinsky et al have shown that HIV-1 infected monocytes have increased production of NO in vitro (Bukrinsky et al, J. Exp. Med. in press (1994)) and Pietreforte and colleagues have reported that HIV-1 gp120 causes human monocytes to produce NO (Pietraforte et al, J. Leuk. Biol. 55:175 (1994)).
The present invention results from a series of experiments designed to study the role of NO on HIV-infection. Since NO binds to the cobalt of cobalamin, cobalamin derivatives were used in these experiments as potential quenchers of NO activity (Akaike et al, Eur. J. Pharmacol. 241:1 (1993); Rand et al, Eur. J. Pharmacol. 241:249 (1993); Rajanayagam et al, Br. J. Pharmacol. 108:3 (1993); Weinberg et al, Blood abstract in press (1994)). Surprisingly, it was observed that various cobalamin derivatives potently inhibited the ability of HIV to cause productive infection of human mononuclear phagocytes (monocytes (Mo) and peritoneal macrophages (Mac)) and normal blood lymphocytes (peripheral blood mononuclear cells (PBL)). The present invention thus provides a novel approach to the prevention and treatment of HIV infection that can be used alone or in combination with antiviral agents, such as reverse transcription inhibitors, currently in use.
The present invention relates to a method of inhibiting human immunodeficiency virus (HIV) infection of a cell comprising contacting the cell with an amount of a cobalamin sufficient to effect the inhibition.
Objects and advantages of the present invention will be clear from the description that follows.